Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. The greatest improvements in treating stage IV lung cancer have come from the capability to both detect and inhibit dominant oncogenes found in subsets of NSCLC, such as ALK and ROS1. Additional oncogenic fusions involving NTRK1 and RET have similar pre-clinical or early clinical evidence of benefit from targeted therapies. Unfortunately all patients who initially respond to targeted therapy experience disease progression due to the development of multiple mechanisms of acquired drug resistance, which are now well established. However, it is not yet understood why the majority of ALK and ROS1+ patients do not undergo complete tumor regression to kinase inhibitor therapy. Our long-term goal is to develop rational effective combinatorial, targeted treatment strategies in cancers harboring oncogene fusions to significantly deepen the initial tumor response and thereby delay acquired resistance. Our preliminary data have uncovered a hitherto unappreciated role for EGFR signaling in oncogene fusion tumors that represents a novel mode of kinome re-programming that is unveiled following oncogene inhibition. The overall objective of this application is to understand the contribution of EGFR signaling, which we believe underlies the eventual development of acquired resistance by cancer cells harboring oncogenic fusions. Our central hypothesis is that upfront targeting of both the fusion kinase (ALK, ROS1, RET or TRKA) and EGFR is necessary to completely inhibit the fusion kinase-EGFR signaling complex and thereby diminish the ability of cancer cells to ultimately develop drug resistance. The rationale for the proposed research is that once we understand the role of wild-type EGFR signaling contributions to cancer cell signaling, cell fate, and oncogene signaling in cancer cells harboring oncogene fusions this will unveil novel strategies for combinatorial EGFR inhibition and fusion kinase inhibition as well as new avenues for combinatorial therapy in other oncogene positive tumors. To test our central hypothesis we propose the following specific aims: (1) determine the efficacy of combinatorial inhibition of the fusion kinase and EGFR in lung cancers harboring oncogene fusions. (2) determine the impact of EGFR activation on downstream signaling in cancer cells harboring gene fusions and (3) determine the molecular mechanism of cross-talk between EGFR and the fusion kinases. The successful outcome of this proposal will modify our current understanding of oncogene addiction by demonstration of interaction between oncogenes (gene fusions) and onco-requisite signaling pathways (wildtype EGFR) and will have a meaningful impact on the field of oncogene targeted therapy by providing new avenues for delaying drug resistance.